2-aralkoxy and 2-alkoxy adenosine derivatives as coronary vasodilators and antihypertensive agents

ABSTRACT

Compounds are disclosed having the formulae: ##STR1## .Iadd.wherein R&#39; is hydrogen, lower alkyl or lower alkoxy; r is 0 or 1 and p is zero to four; and .Iaddend. 
     wherein R 1  is selected from the group, consisting of radicals represented by the general formulae: ##STR2## wherein Y is selected from the group consisting of lower alkyl, lower alkoxy, and halogen; Z is oxygen, sulfur or --NH, Q is --CH or nitrogen; a is zero or an integer of from one to three; and 
     wherein, R 2  is selected from the group consisting of hydrogen and straight chain, branched and cyclic hydrocarbyl radicals having from one to four carbon atoms, and optionally substituted with a hydroxyl radical; and 
     wherein X is two hydrogen atoms or oxygen and B is selected from oxygen and nitrogen, and pharmaceutically acceptable salts thereof, with the proviso that when X is two hydrogen atoms, B is oxygen, and with the further proviso that when B is oxygen then R 1  cannot be a phenyl or a substituted phenyl radical. Pharmaceutical preparations using these compounds and a method for inducing an adenosine response mediated by the adenosine A 2  receptor by administering these compounds are also disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to certain 2-substituted adenosinederivatives which have beneficial cardiovascular and antihypertensiveactivity in mammals, including humans and domestic animals. The presentinvention is also directed to a process for making said compounds.

2. Brief Description of the Prior Art

Adenosine has been known for a long time to possess certaincardiovascular, and particularly coronary dilator activity. In an effortto obtain adenosine analogs of greater potency, or longer duration ofactivity, or both, many analogs of this naturally occurring nucleosidehave been synthesized and tested.

Moreover, numerous studies have been conducted in order to elucidate thebiochemical mechanism of action of adenosine and its analogs, andseveral theories and hypotheses have been proposed regarding biochemicalpathways and receptor sites.

For discussion of current theories regarding the foregoing, reference ismade to the following articles and publications: Adenosine Receptors:Targets for Future Drugs, by John W. Daly, Journal of MedicinalChemistry, 25, 197 (1982); Cardiovascular Effects of Nucleoside Analogs,by Herman H. Stein and Pitambar Somani, Annals New York Academy ofSciences, 225, 380 (1979); Coronary Dilatory Action of AdenosineAnalogs: a Comparative Study, by. G. Raberger, W. Schutz and O. Kraupp,Archives internationales de Pharmacodynmie et de Therpie 230, 140-149(1977); chapter 6 of the book titled: Regulatory Function of Adenosine,(pages 77-96), R. M. Berne, T. W. Rall and R. Rubio editors, MartinusNijhoff publishers, The Hague/Boston/London; and EthylAdenosine-5'-carboxylate. A Potent Vasoactive Agent in the Dog, byHerman H. Stein. Journal of Medicinal Chemistry, 16, 1306 (1973);Modification of the 5' Position of Purine Nucleosides. 2. Synthesis andSome Cardiovascular Properties ofAdenosine-5'(N-substituted)carboxamides, by Raj. N. Prasad et al.,Journal of Medicinal Chemistry, 23 313 (1980), and Modification of the5' Position of Purine Nucleosides. 1. Synthesis and BiologicalProperties of Alkyl Adenosine-5'-carboxylates by Raj N. Prasad et al.,Journal of Medicinal Chemistry, 19, 1180 (1976).

Still more adenosine derivatives having beneficial cardiovascularactivity are described in another application for United States LettersPatent of the present inventors, Ser. No. 601,435, filed on Apr. 18,1984, now abandoned, Ser. No. 742,565, filed on Jun. 12, 1985, and Ser.No. 625,450, filed on Jun. 28, 1984.

Adenosine receptors have been subdivided into two subtypss: A₁receptors, which inhibit adenylate cyclase, and A₂ receptors, whichstimulate adenylate cyclase. It is thought that coronary vasodilation ismediated by A₂ receptor activation [see, e.g., Haleen, S., et. al., LifeSci., 36, 127-137 (1985)]. In order to minimize side effects associatedwith activation of A₁ receptors, it is a goal of pharmaceutical researchto identify compounds highly selective for A₂ receptors.

Among a series of related compounds, one early compound claimed topossess coronary vasodilatory activity was 2-phenylaminoadenosine(CV-1808) [see Marumoto, R., et. al., Chem. Pharm. Bull., 23, 759(1975)]. More recently, a series of N⁶ -substituted adenosinederivatives were disclosed as having high A₂ affinity and selectivity[see Trivedi, B. K., et. al., J. Med. Chem., 31, 271-273 (1988), andBridges, A., et. al., J. Med. Chem., 31, 1282-1285 (1988)]. Anotherseries of 2,5'-disubstituted adenosine derivatives have been disclosedas A₂ agonists (European Patent Application EP-277-917-A).

Many of the known adenosine derivatives are less than satisfactory astheraupeutics agents, due to low activity, short duration of effect,toxicity or undesirable side effects. In this light, there is acontinuing interest in identifying agents which posses an desiredprofile of highly selective and potent adenosine A₂ receptor activitywith minimal toxicity. The compounds of the present invention constitutea step in this direction.

SUMMARY OF THE INVENTION

There have now been discovered certain novel compounds having activityas A₂ adenosine receptor agonists and having the structural formula:##STR3## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy,.Iaddend.R₁ is selected from the group, consisting of branched,straight-chained or cyclic hydrocarbyl radicals, having from one to sixcarbon atoms, and radicals represented by the general formulae: ##STR4##wherein Y is selected from the group consisting of lower alkyl, loweralkoxy, carboxy-lower alkyl and halogen; Z is oxygen, sulfur or --NH, Qis --CH or nitrogen, .Iadd.r is 0 or 1 and p is zero or an integer offrom one to four; .Iaddend.a is zero or an integer of from one to three;n is zero or an integer of from one to three; and m is an integer offrom three to six; and

wherein, when R₁ is a hydrocarbyl radical, it may be substituted withone or two radicals represented by the above general formula orsubstituted with --OR₃, wherein R₃ is hydrogen or lower alkyl, havingfrom one to ten carbon atoms; R₂ is selected from the group consistingof hydrogen and straight chain, branched and cyclic hydrocarbyl radicalshaving from one to four carbon atoms, and optionally substituted with ahydroxyl radical; and

wherein X is two hydrogen atoms or oxygen and B is selected from oxygenand nitrogen, with the proviso that when X is two hydrogen atoms, B isoxygen, and with the further proviso that when R₃ is present or R₁ is abranched or straight-chained hydrocarbyl radical, then R₁ must besubstituted with one of the above radicals, and with the still furtherproviso that when B is oxygen, then R₁ cannot be a phenyl or asubstituted phenyl radical.

DETAILED DESCRIPTION OF THE INVENTION

Certain derivatives of adenosine have been found in accordance with thepresent invention to selectively activate A₂ adenosine receptors and topossess significant cardiovascular and/or vasodilatory anti-hypertensiveactivity. The compounds used in the present invention are selected fromthe group of stereoisomers or mixtures thereof of compounds havingactivity as adenosine A₂ receptor agonists are represented by theformula: ##STR5## wherein .Iadd.R' is hydrogen, lower alkyl or loweralkoxy, .Iaddend.R₁ is selected from the group, consisting of branched,straight-chained or cyclic hydrocarbyl radicals, having from one to sixcarbon atoms, and radicals represented by the general formulae: ##STR6##wherein Y is selected from the group consisting of lower alkyl, loweralkyl, carboxy-lower alkyl and halogen; Z is oxygen, sulfur or --NH; Qis --CH or nitrogen; .Iadd.r is 0 or 1 and p is zero or an integer offrom one to four, .Iaddend.a is zero or an integer of from one to three;n is zero or an integer of from one to three; and m is an integer offrom three to six; and

wherein, when R₁ is a hydrocarbyl radical, it may be substituted withone or two radicals represented by the above general formula orsubstituted with --OR₃, wherein R₃ is hydrogen or lower alkyl, havingfrom one to ten carbon atoms; R₂ is selected from the group consistingof hydrogen and straight chain, branched and cyclic hydrocarbyl radicalshaving from one to four carbon atoms, and optionally substituted with ahydroxyl radical; and

wherein X is two hydrogen atoms or oxygen and B is selected from oxygenand nitrogen, with the proviso that when X is two hydrogen atoms, B isoxygen, and with the further proviso that when R₃ is present or R₁ is abranched or straight-chained hydrocarbyl radical, then R₁ must besubstituted with one of the above radicals, and with the still furtherproviso that when B is oxygen, then R₁ cannot be a phenyl radical or asubstituted phenyl radical.

As used herein, the term "lower" as in "lower alkyl" refers to compoundshaving from 1 to 10 carbon atoms. The preferred lower alkyl radicalshave from 1 to 4 carbon atoms. As used herein, the term "halogen" refersto bromide, chloride, fluoride and iodide radicals. Compounds fallingwithin the scope of this invention are as follows:

2-benzyloxyadenosine

2-(2-phenylethoxy)adenosine

2-(5-phenylpentoxy)adenosine

2-cyclopentyloxyadenosine

2-cyclohexyloxyadenosine

2-(2-phenylethoxy)-5'-(N-ethylcarboxamido)adenosine

2-[2-(4-fluorophenyl)ethoxy]-5'-(N-ethylcarboxamido)adenosine

2-(3-phenylpropoxy)adenosine

2-cyclohexylethoxyadenosine

2-(4-phenylbutoxy)adenosine

2-(3,4,5-trimethoxyphenylethoxy)adenosine

2-[2-(2-thienyl)ethoxy]adenosine

2-[2-(3-thienyl)ethoxy]adenosine

2-(4-phenylbutoxy)adenosine

2-(2-pyridylethoxy)adenosine

2-(2-cyclohexylethoxy)adenosine

2-[2-(2-methylphenyl)ethoxy]adenosine

2-[2-(2-methoxyphenyl)ethoxy]adenosine

2-[2-(3-methoxyphenyl)ethoxy]adenosine

2-[2-(4-methoxyphenyl)ethoxy]adenosine

2-[2-(4-fluorophenyl)ethoxy]adenosine

2-[2-(3-indolyl)ethoxy]adenosine

2-[2-(1-naphthyl)ethoxy]adenosine

2-[2-(2-naphthyl)ethoxy]adenosine

2-(2,2-diphenylethoxy)adenosine

2-(4-biphenylethoxy)adenosine

2-(4-aminophenylethoxy)adenosine

2-(4-hydroxyphenylethoxy)adenosine

2-(2-indanyloxy)adenosine

2-2R-(1,2,3,4-tetrahydronaphthyloxy)adenosine

2-2S-(1,2,3,4-tetrahydronaphthyloxy)adenosine

2-(2-phenyl-1-propoxy)adenosine

2-(-2-phenyl,2R-hydroxyethoxy)adenosine

2-(2-phenyl,2S-hydroxyethoxy)adenosine

2-(-2-phenyl,2R-methoxyethoxy)adenosine

2-(-2-phenyl,2S-methoxyethoxy)adenosine

2-(2R-phenyl,1-butoxy)adenosine

2-(2S-phenyl,1-butoxy)adenosine

2-[(4-carboxyethylphenyl)ethyoxy]adenosine

2-[(2-butylphenyl)ethoxy]adenosine

The invention is further illustrated by the following examples which areillustrative of various aspects of the invention, and are not intendedas limiting the scope of the inventions defined by the appended claims.

The invention also encompasses a method of preparation of the subjectcompounds, pharmaceutical compositions of the subject compounds and amethod for inducing an adenosine A₂ response by administering thesubject compounds to a patient. The general method of preparation of theabove compounds comprises the reaction of a 2-haloadenosine derivativeshown below with an alkali metal salt of .[.R₁ OH..]. ##STR7##

Details of the synthesis, together with modifications and variationsspecifically tailored for particular compounds, are set out more fullyin the specific examples which follow.

EXAMPLE 1 Preparation of 2-(3-phenyl-1-propoxy)adenosine

To a cold (10 C) solution of 3-phenyl-1-propanol (6 mL, 4.4 mmoles) and70 mL of dry tetrahydrofuran was added n-butyllithium 1.6M in hexanes(25 mL, 40.0 mmoles) via syringe. The above solution was stirred for 15minutes at room temperature followed by the addition of2-chloro-2',3'-O-isopropylideneadenosine (3.0 g, 8.8 mmoles). Themixture was refluxed for 4 days (HPLC showed less then 5% startingmaterial). The solvents were removed in vacuo to give a dark brownsyrup. Water (50 mL) was added and the pH adjusted to 7 with 4N HCl. Theaqueous phase was extracted with ethyl acetate (4×50 mL) and the organicextracts dried over magnesium sulfate. The drying agent was filtered offand the solvents removed in vacuo to afford a brown syrup. This waspurified by flash chromatography on silica gel (40-60μ) using a stepgradient of chloroform to 2% methanol in chloroform. The fractions thatshowed product were collected and the solvents removed in vacuo to givea light brown syrup (blocked nucleoside). The syrup was dissolved in 80mL of methanol. To this solution was added 10 mL water and 10 mL 98%formic acid and boiled until HPLC showed no blocked nucleoside. Sodiumbicarbonate was added until a pH of 7 was achieved. The solvents wereremoved in vacuo. To the residue was added 2-propanol and the insolublesalts were filtered off. The 2-propanol was removed in vacuo and theproduct purified by preparative HPLC on a C-18 column, using a lineargradient of 50-70% methanol in water to yield 700 mg (20%) of acolorless solid. The characteristic NMR spectral peaks are: (60 MHz,DMSO-d₆) δ 1.95 (m, 2H), 2.63 (m, 2H), 3.5-5.4 (m, 8H), 4.15 (t, 2H),5.78 (d, 2H), 7.20 (m, 7H), 8.15 (s, 1H). m.p. 100-102 C.

The above procedure was attempted using sodium hydride in place ofn-butyllithium, which gave less than 5% yield by HPLC.

EXAMPLE 2 Preparation of 2-[2-(4-fluorophenyl)ethoxy]adenosine

The general procedure of Example 1 was followed, using the followingreactants: 4-Fluorophenyl alcohol (4.2 mL, 33.5 mmoles); 1.6Mn-butyllithium (20.0 mL, 31.9 mmoles);2-chloro-2',3'-O-ethoxymethylideneadenosine (3.0 g, 8.4 mmoles). Allconditions were identical with the exception of the hydrolysis and finalpurification conditions. Hydrolysis was achieved using concentratedacetic acid (5 mL). Final purification was done in the same manner,using a linear gradient of 50-68% methanol to yield 1.3 g (36%) ofcolorless solid. The characteristic NMR spectral peaks are: (60 MHz,DMSO-d₆) δ 3.12 (t, 2H), 3.55-5.55 (m, 8H), 4.58 (t, 2H), 5.88 (d, 1H),7.05-7.41 (m, 6H), 8.08 (s, 1H). m.p. 148-150 C.

EXAMPLE 3 Preparation of 2-Cyclopentyloxyadenosine

The general procedure of Example was followed, using cyclopentanol inplace of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are:(60 MHz, DMSO-d₆) δ 1.80 (s, 8H), 3.50-5.48 (m, 9H), 5.80 (d, 1H), 7.20(s, 2H), 8.14 (s, 1H). m.p. 147-150 C.

EXAMPLE 4 Preparation of 2-Cyclohexyloxyadenosine

The general procedure of Example 1 was followed, using cyclohexanol inplace of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are:(60 MHz, DMSO-d₆) δ 1.00-2.10 (m, 10H), 3.42-5.52 (m, 9H), 5.71 (d, 1H),7.15 (s, 2H), 8.02 (s, 1H). m.p. 147 C.

EXAMPLE 5 Preparation of 2-(2-Cyclohexylethoxy)adenosine

The general procedure of Example was followed, using 2-cyclohexylethanolin place of 3-phenyl-1-propanol. The characteristic NMR spectral peaksare: (60 MHz, DMSO-d₆) δ 0.88-1.95 (m, 13H), 3.50-5.60 (m,8H), 4.64 (t,2H), 5.89 (d, 1H), 7.20 (s, 2H), 8.10 (s, 1H). m.p. 185-187 C.

EXAMPLE 6 Preparation of 2-benzyloxyadenosine

The general procedure of Example was followed, using benzyl alcohol inplace of 3-phenyl-1-propanol. The characteristic NMR spectral peaks are:(60 MHz, DMSO-d₆) δ 3.40-5.45 (m, 8H), 5.27 (s, 2H), 5.66 (d, 1H), 7.32(m, 7H), 8.09 (s, 1H), m.p. 172-75 C.

EXAMPLE 7 Preparation of 2-(2-phenylethoxy)adenosine

The general procedure of Example 1 was followed, using phenethyl alcoholin place of 3-phenyl-1-propanol. The characteristic NMR spectral peaksare: (60 MHz, DMSO-d₆) δ 3.00 (t, 2H), 3.45-5.45 (m, 10H), 5.77 (d, 1H),7.29 (s, 7H), 8.13 (s, 1H). m.p. 95-97 C.

EXAMPLE 8 Preparation of 2-[2-(2-methoxyphenyl)ethoxy]adenosine

The general procedure of Example 1 was followed, using2-(2-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.03 (t, 2H),3.6-5.6 (m, 10H), 3.8 (s, 3H), 5.86 (d, 1H), 6.8-7.52 (m, 6H), 8.17 (s,1H). m.p. 126-130 C.

EXAMPLE 9 Preparation of 2-[2-(3-methoxyphenyl)ethoxy]adenosine

The general procedure of Example 1 was followed, using2-(3-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.0 (t, 2H),3.6-5.65 (m, 10H), 3.76 (s, 3H), 5.86 (d, 1H), 6.7-7.5 (m, 6H), 8.18 (s,1H). m.p. 103-105 C.

EXAMPLE 10 Preparation of 2-[2-(4-methoxyphenyl)ethoxy]adenosine

The general procedure of Example was followed, using2-(4-methoxyphenyl)ethanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 2.95 (t, 2H),3.5-5.52 (m, 8H), 3.74 (s, 3H), 4.4 (t, 2H), 5.86 (d, 1H), 6.86 (d, 2H),7.25 (d, 2H), 7.33 (2, 2H), 8.2 (s, 1H).

EXAMPLE 11 Preparation of 2-[2-(2-methylphenyl)ethoxy]adenosine

The general procedure of Example was followed, using2-methylphenylethanol in place of 3-phenyl-I-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 2.33 (s, 3H),3.04 (t, 2H), 3.5-5.55 (m, 8H), 4.45 (t, 2H), 5.85 (d, 1H), 7.2 (s, 4H),7.3 (s, 2H), 8.19 (s, 1H). m.p. 166-168 C.

EXAMPLE 12 Preparation of 2-[2-(3,4,5-trimethoxyphenyl)ethoxy]adenosine

The general procedure of Example 1 was followed, using3,4,5-trimethoxyphenylethanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 2.95 (t, 2H),3.5-5.58 (m, 8H), 4.45 (t, 2H), 5.72 (d, 1H), 6.65 (s, 2H), 7.28 (s,2H), 8.16 (s, 1H). m.p. 110-112 C.

EXAMPLE 13 Preparation of 2-[2-(2-thienyl)ethoxy]adenosine

The general procedure of Example was followed, using2-(2-thienyl)ethanol in place of 3-phenyl-1-propanol. The characteristicNMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.19 (t, 2H), 3.5-5.5 (m,8H), 4.44 (t, 2H), 5.8 (d, 1H), 6.88-7.43 (m, 5H), 8.26 (s, 1H). m.p.104-106 C.

EXAMPLE 14 Preparation of 2-[2-(3-thienyl)ethoxy]adenosine

The general procedure of Example was followed, using2-(3-thienyl)ethanol in place of 3-phenyl-1-propanol. The characteristicNMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.1 (t, 2H), 3.3-5.6 (m,8H), 4.5 (t, 2H), 5.85 (d, 1H), 7.0-7.58 (m, 5H), 8.22 (s, 1H). m.p.99-102 C.

EXAMPLE 15 Preparation of 2-[2-(1-naphthyl)ethoxy]adenosine

The general procedure of Example was followed, using2-(1-naphthyl)ethanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.45-5.5 (m,10H), 4.5 (t, 3H), 5.84 (d, 1H), 7.42 (s, 2H), 7.35-8.38 (m, 7H), 8.2(s, 1H). m.p. 125-130 C.

EXAMPLE 16 Preparation of 2-[2-(3-indolyl)ethoxy]adenosine

The general procedure of Example 1 was followed, using2-(3-indolyl)ethanol in place of 3-phenyl-1-propanol. The characteristicNMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.24 (t, 2H), 3.52-3.58 (m,8H), 4.54 (t, 2H), 5.88 (d, 1H), 6.9-7.7 (m, 7H), 8.12 (s, 1H), 10.12(s, 1H). m.p. 138-140 C.

EXAMPLE 17 Preparation of 2-(2-phenyl-1-propoxy)adenosine

The general procedure of Example 1 was followed, using2-phenyl-1-propanol in place of 3-phenyl-1-propanol. The characteristicNMR spectral peaks are: (60 MHz, DMSO-d₆) δ 1.36 (d, 3H), 3.1-5.55 (m,11H), 5.85 (d, 1H), 7.35 (s, 7H), 8.2 (s, 1H). m.p. 135 C

EXAMPLE 18 Preparation of 2-[(2-[(2R)-phenyl-1-butoxy]adenosine

The general procedure of Example 1 was followed, using(2S)-phenyl-1-butanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 0.82 (t, 3H),1.7 (m, 2H), 3.0 (m, 1H), 3.45-5.5 (m, 8H), 4.4 (d, 2H), 5.82 (d, 1H),7.32 (s, 6H), 8.16 (s, 1H). m.p. 155 C.

EXAMPLE 19 Preparation of 2-[(2S)-phenyl-1-butoxy]adenosine

The general procedure of Example 1 was followed, using(2S)-phenyl-1-butanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 0.8 (t, 3H),1.73 (m, 2H), 2.95 (m, 1H), 3.6-5.57 (m, 8H), 4.4 (d, 2H), 5.89 (d, 1H),7.32 (s, 6H), 8.22 (s, 1H). m.p. 108-110 C.

EXAMPLE 20 Preparation of 2-(4-phenyl-1-butoxy)adenosine

The general procedure of Example 1 was followed, using4-phenyl-1-butanol in place of 3-phenyl-1-propanol. The characteristicNMR spectral peaks are: (60 MHz, DMSO-d₆) δ 1.75 (m, 4H), 2.61 (m, 2),3.5-5.55 (m, 10H), 5.81 (d, 1H), 7.27 (s, 7H), 8.16 (s, 1H). m.p. 93-96C

EXAMPLE 21 Preparation of 2-(5-phenyl-1-pentoxy)adenosine

The general procedure of Example 1 was followed, using5-phenyl-1-pentanol in place of 3-phenyl-1-propanol. The characteristicNMR spectral peaks are: (60 MHz, DMSO-d₆) δ 1.35-2.07 (m, 6H), 2.72 (t,2H), 3.6-5.58 (m, 8H), 4.33 (t, 2H), 5.88 (d, 1H), 7.23 (s, 7H), 8.1 (s,1H). m.p. 102-104 C.

EXAMPLE 22 Preparation of2-(2-phenyl)ethoxy-5'-N-ethylcarboxamidoadenosine

To a mixture of 2-phenylethanol (3.14 mL, 26.3 mmoles) in drytetrahydrofuran (50 mL) was added n-butyllithium (16.4 mL, 26.2 mmoles)dropwise. This mixture was allowed to stir 15 min. at room temperature.The 2-chloro-5'-N-ethylcarboxamidoadenosine (1.5 g, 4.38 mmoles) wasadded in one portion and the mixture refluxed for 72 hours. Water (50mL) was added. The precipitate was filtered off and the filtrateextracted with ethyl acetate (4×50 mL). The organic phases were driedwith magnesium sulfate. The drying agent was removed by filtration andthe solvents removed in vacuo to give a foam. Purification on apreparative HPLC C-18 column, using a linear gradient of 50-70%methanol/water gave a colorless solid. The characteristic NMR spectalpeaks are: (60 MHz, DMSO-d₆) δ 1.07 (t, 3H), 3.39 (m, 4H), 4.1-4.77 (m,5H), 5.5-5.78 (m, 2H), 5.9 (d, 1H), 7.32 (s, 5H), 7.46 (s, 2H), 8.2 (s,1H), 8.9 (t, 1H). m.p. 130-133 C.

EXAMPLE 23 Preparation of 2-(3-cyclohexyl)propoxyadenosine

The general procedure of Example I was followed, using3-cyclohexyl-1-propanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 0.7-1.9 (m,15H), 3.55-5.55 (m, 10H), 5.8 (d, 1H), 7.23 (s, 2H), 8.14 (s, 1H).

EXAMPLE 24 Preparation of 2-[2-(2-naphthyl)ethoxy]adenosine

The general procedure of Example was followed, using2-(2-naphthyl)ethanol in place of 3-phenyl-1-propanol. Thecharacteristic NMR spectral peaks are: (60 MHz, DMSO-d₆) δ 3.3 (t, 2H),3.42-5.5 (m, 8H), 4.67 (t, 2H), 5.84 (d, 1H), 7.22-8.05 (m, 7H), 7.89(s, 2H), 8.18 (s, 1H).

EXAMPLE 25

Assays of the cardiovascular potency of the above compounds at the A₁receptors of the SA node and at the A₂ receptor of the coronary arteryemployed perfused hearts from female Sprague-Dawley guinea pigs in anisolated Langendorff heart preparation. An assay consists of an infusionof a spectophotometrically standardized solution of test compounddirectly into the aortic cannula at rates increasing stepwise every 5minutes. Collection of the total cardiac effluent during the first halfof each infusion period provides a measure of coronary flow (A₂ effect).The concentration of test compound required to produce a half-maximalincrease in coronary flow is determined. Registration of the ECGassesses the effect of the test compound on SA node (stimulus to Qinterval, A₁ effect). The concentration of test compound required toproduce a half-maximal prolongation of stimulus to Q interval isdetermined. Table I summarizes the resultant data, using adenosine as areference compound. The ratio of A₁ and A₂ effects of test compounds arecalculated to provide the selectivity ratio.

                  TABLE I                                                         ______________________________________                                                 Coronary                                                                      Blood Flow   SQ Prolongation                                                  Increase (A.sub.2)                                                                         (A.sub.1)   Selectivity                                 Example  EC.sub.50 (nM)                                                                             ED.sub.50 (nM)                                                                            (A.sub.1 /A.sub.2)                          ______________________________________                                        Adenosine                                                                              49.7         3162        63.6                                        6        419.3        6310        15                                          7        2.8          19953       7126                                        3        91.7         79433       866                                         4        656.9        100000      152                                         22       1.3          14962       11509                                       1        61.3         19953       326                                         13       3.7          11885       3212                                        14       3.4          18836       5540                                        20       9.9          7356        743                                         15       5.1          8414        1650                                        17       9.0          53088       5899                                        12       22.0         47315       2151                                        5        1.0          8630        8630                                        11       3.8          25119       6610                                        9        2.6          16218       6238                                        18       373.7        18836       50                                          19       31.4         27384       872                                         8        32.0         35481       1109                                        21       6.4          4597        718                                         2        0.9          25606       29432                                       16       9.8          14125       1441                                        10       1.4          19724       14089                                       23       2.2          3758        1708                                        24       0.5          11416       22832                                       ______________________________________                                    

This data shows the high degree of potency and selectivity of thesubject compounds in increasing coronary blood flow at lowconcentrations while having comparatively little effect on the SQprolongation. The ratios calculated show the marked A₂ selectivity ofthe subject compounds.

It is essential that the compounds herein be capable of bindingselectively to A₂ adenosine receptors e.g., in a human.2-phenylethoxy-5'-(N-ethylcarboxamido)adenosine and2-(4-fluorophenyl)ethoxyadenosine 2-[2-(4-methoxyphenyl)ethoxy]adenosineand 2-[2-(2-naphthyl)ethoxy]adenosine are particularly preferredcompounds because of the high affinity and selectivity for A₂ adenosinereceptors. It is believed that the compounds herein will be useful ascardiac vasodilators in humans and other animals.

Various modifications of the herein disclosed invention, in terms ofstructural modifications of the invented compounds and also in terms ofmaking or using the same, may become readily apparent to those skilledin the art in light of the above disclosure. For example, the compoundsof the present invention may be administered as pharmaceuticallyacceptable salts.

Inasmuch as the compounds of the present invention are useful as cardiacvasodilators, cardiovascular, and particularly as anti-hypertensiveagents in mammals, domestic animals and humans various modes ofadministering the compounds will be apparent to a person having averageskill in the art. Such modes of administering the compounds include oraland topical administration, and intravenous infusion. One having averageskill in the art may readily prepare suitable formulations for theabovementioned and other modes of administering the compounds of theinvention.

In light of the foregoing, the scope of the present invention should beinterpreted solely from the following claims, as such claims are read inlight of the disclosure.

We claim:
 1. A compound selected from the group of stereoisomers ormixtures thereof of compounds having the formulae: ##STR8## wherein.Iadd.R' is hydrogen, lower alkyl or lower alkoxy, .Iaddend.R₁ is##STR9## wherein Y is selected from the group consisting of lower alkyl,lower alkoxy, and halogen; Z is oxygen, sulfur or --NH, Q is --CH ornitrogen; .Iadd.r is 0 or 1 and p is zero or an integer of from one tofour; .Iaddend.a is an integer from 0 to 3; andwherein R₂ is selectedfrom the group consisting of hydrogen and straight, branched or cyclichydrocarbyl radicals having from 1 to 4 carbon atoms; and wherein x is 2hydrogen atoms or oxygen and B is selected from the group consisting ofoxygen and nitrogen, with the proviso that when x is 2 hydrogen atoms, Bis oxygen and with the further proviso that when B is oxygen then R₂cannot be a phenyl or phenyl substituted with one or more substituentsat positions 2-, 3-, 4- and 5-.
 2. A compound of claim 1 wherein a iszero.
 3. A compound of claim 1 wherein Y is halogen.
 4. A compound ofclaim 1 wherein Q is --CH.
 5. A compound of claim 1 wherein R₁ isphenylethyl.
 6. A compound of claim 1 wherein R₁ is 4-fluorophenylethyl.7. A compound of claim 1 wherein R₁ is 4-methoxyphenylethyl.
 8. Acompound of claim 1 wherein R₁ is 2-(2-naphthyl)ethyl.
 9. A compound ofclaim 1 wherein R₂ is ethyl and R₁ is phenylethyl. 10.2-(2-phenyl)ethoxyadenosine. 11.2-(2-phenyl)ethoxy-5'-N-ethylcarboxamidoadenosine. .[.12.2-[2-(4-fluorophenyl)ethoxy]adenosine..]..[.13.2-[2-(4-methoxyphenyl)ethoxy]adenosine..]..[.14.2-[2-(2-naphthyl)ethoxy]adenosine..].15.2-(2-cyclohexyl)ethoxyadenosine.
 6. A method for inducing an adenosineresponse indicated by an adenosine A₂ receptor in a human or animal,comprising the step of administering to a human or an animal in need ofsuch treatment, an effective amount of a compound having the formulae:##STR10## wherein .Iadd.R' is hydrogen, lower alkyl or lower alkoxy,.Iaddend.R₁ is ##STR11## wherein Y is selected from the group consistingof lower alkyl, lower alkoxy, and halogen; Z is oxygen, sulfur or --NH,Q is --CH or nitrogen; .Iadd.r is 0 or 1 and p is zero or an integer offrom one to four; .Iaddend.a is an integer from 0 to 3; andwherein R₂ isselected from the group consisting of hydrogen and straight, branched orcyclic hydrocarbyl radicals having from 1 to 4 carbon atoms; and whereinx is 2 hydrogen atoms or oxygen and B is selected from the groupconsisting of oxygen and nitrogen, with the proviso that when X is 2hydrogen atoms, B is oxygen with the further proviso that when B isoxygen then R₂ cannot be a phenyl or phenyl substituted with one or moresubstituents at positions 2-, 3-, 4 and 5-. .Iadd.17.2-[2-(4-fluorophenyl)ethoxy]adenosine. .Iaddend..Iadd.18.2-[2-(4-methoxyphenyl)ethoxy]adenosine. .Iaddend..Iadd.19.2-[2-(2-naphthyl)ethoxy]adenosine. .Iaddend.